Novel clerodane-type diterpenoid Cintelactone A suppresses lipopolysaccharide -induced inflammation by promoting ubiquitination, proteasomal degradation of TRAF6

被引：8

作者：

Di, Qianqian ^{[1
]}

Zhao, Xibao ^{[1
]}

Zhang, Ruihan ^{[2
]}

Ma, Xingyu ^{[1
]}

Liang, Xinxin ^{[2
]}

Li, Xiaoli ^{[2
]}

Gao, Junbo ^{[2
]}

Tang, Haimei ^{[1
]}

Chen, Weilin ^{[1
]}

Xiao, Weilie ^{[2
]}

机构：

[1] Shenzhen Univ, Dept Immunol, Guangdong Prov Key Lab Reg Immun & Dis, Sch Med, Shenzhen 518060, Peoples R China

[2] Yunnan Univ, Sch Chem Sci & Technol, Key Lab Med Chem Nat Resource, Minist Educ & Yunnan Prov, Kunming 650091, Yunnan, Peoples R China

来源：

PHARMACOLOGICAL RESEARCH | 2021年 / 164卷

基金：

中国国家自然科学基金;

关键词：

Cintelactone A; LPS-induced inflammation; TRAF6; Ubiquitination; Sepsis;

D O I：

10.1016/j.phrs.2020.105386

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Cellular inflammation is the underlying cause of several diseases and development of a safe and effective anti-inflammatory drug is need-of-the hour for treatment of diseases like lung inflammation. Callicarpa integerrima Champ. is a well-known herbal medicine with hemostatic and anti-inflammatory functions. However, the exact ingredient exhibiting anti-inflammatory activity in C. integerrima Champ. is largely unknown. Here, we first isolated, purified and characterized a novel clerodane-type diterpenoid Cintelactone A (CA) from C. integerrima Champ. We demonstrated that CA could significantly inhibit lipopolysaccharide (LPS)-induced pro-inflammatory cytokines and mediators production both in mouse peritoneal macrophages and THP1 cells. Consistently, CA also relieved inflammation and reduced LPS-induced lung injury in mice. We systematically elucidated the mechanism of action as well. CA interacted with Arg78 of tumor necrosis factor receptor-associated factor 6 (TRAF6) by hydrogen bonding. It further promoted the K48-linked ubiquitination and proteasomal degradation of TRAF6, and suppressed the activation of NF-kappa B and MAPKs signaling pathways. Collectively, our study reveals that new clerodane-type diterpenoid CA suppresses LPS-induced inflammation by promoting TRAF6 degradation, suggesting that CA as the potential therapeutic candidate for the treatment of inflammation associated diseases.

引用

页数：12

共 41 条

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